STOP-IgAN Disappoints With No Benefit From Additional Rx

Pam Harrison

December 15, 2015

The addition of an immunosuppressive regimen to ongoing comprehensive supportive care does not benefit patients with immunoglobulin A (IgA) nephropathy characterized by moderate proteinuria and chronic kidney disease stages 1 to 3, final results from the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) study indicate.

The study was published in the December 3 issue of the New England Journal of Medicine.

"Although the addition of immunosuppressive therapy to supportive care was superior to supportive care alone in inducing remission of proteinuria in a proportion of patients, there was no significant difference between the two study groups with respect to the second primary end point of decreasing the rate of fast decreases in the [estimated glomerular filtration rate (eGFR)]," Thomas Rauen, MD, from the Division of Nephrology and Clinical Immunology, Rheinisch-Westf&aauml;lische Technische Hochschule Aachen, Germany, and fellow STOP-IgAN investigators report.

Moreover, rates of severe infections, impaired glucose tolerance, and weight gain totaling more than 5 kg in the first year of treatment were all numerically higher in patients who received additional immunosuppression, and one patient in the immunosuppressive group died of sepsis during the trial. Two cases of malignant neoplasm were also observed in patients receiving additional immunosuppression.

The STOP-IgAN Trial

The STOP-IgAN trial was a randomized controlled trial with a two-group parallel design. During a 6-month run-in phase, all patients received comprehensive supportive care consisting primarily of the use of renin-angiotensin system blockers to lower blood pressure to less than 125/75 mm Hg.

"If proteinuria remained above the target of 0.75 g per day of urinary protein excretion despite blood-pressure control, the dose of the renin–angiotensin system blocker was increased to the maximum approved daily dose or to the highest dose at which the patient did not have unacceptable side effects," the authors explain. Where needed, total cholesterol was lowered to less than 200 mg/dL (5.2 mmol/L) with statin therapy.

At the end of 6 months of supportive care, patients who had persistent proteinuria of at least 0.75 g/day (but less than 3.5 g/day) were randomly assigned to continue with supportive care alone or to receive an additional immunosuppressive regimen.

Those with an eGFR of between 30 and 59 mL/minute per 1.73 m2 received cyclophosphamide 1.5 mg/kg a day for 3 months, followed by azathioprine, 1.5 mg/kg a day, from 4 to 36 months, the study endpoint. They also received oral prednisolone, 40 mg/day, which was tapered to 10 mg/day during the first 3 months of the study.

Patients with an eGFR of at least 60 mL/minute per 1.73 m2 who were enrolled in the final 36 months of the study received glucocorticoid monotherapy at various doses. In total, 76 patients in the supportive care group and 78 patients in the immunosuppression group completed 3 years of the trial.

More patients (17%) in the immunosuppressive group achieved the first primary endpoint of full clinical remission at the end of 3 years than those who received supportive care alone (5%; P = .01); however, the investigators report that the higher rate of clinical remission was entirely driven by remission of proteinuria.

No "Significant" Effect on eGFR

The second primary endpoint was a decrease in the eGFR of at least 15 mL/minute per 1.73 m2. Here there was no significant difference in the percentage of patients who met this endpoint in the supportive care group (28%), vs the immunosuppressive group (26%), based on the full analysis set.

Nor were any significant differences observed between the two treatment groups in the mean absolute change in eGFR, the mean annual change in the slope of the reciprocal of serum creatinine concentration, or the number of patients who had a decrease in the eGFR of at least 30 mL/minute per 1.73 m2.

The number of patients who reached end-stage renal disease was also not significantly different between the two groups.

"Despite the significant, though moderate, effect on proteinuria, we did not observe a significant effect of immunosuppressive therapy on a decrease in the eGFR over the 3-year study period either on the basis of the primary end point of an eGFR decrease of 15 ml per minute per 1.73 m2 or more from the baseline eGFR or on the basis of various secondary eGFR end points," the authors write.

"Given a mean baseline eGFR of approximately 60 ml per minute per 1.73 m2, our primary end point corresponds to a loss of renal function of approximately 25%."

The authors caution, however, that their findings do not apply to patients with proteinuria greater than 3.5 g per day, as such patients are at very high risk for progressive disease and have a particularly good response to glucocorticoids, according to several reports.

Very Important Study

Ali Gharavi, MD, chief of the Division of Nephrology at the Columbia University College of Physicians and Surgeons, New York City, told Medscape Medical News that the STOP-IgAN was a "very important study," as it is necessary to prospectively evaluate the effect that immunosuppression might have on disease progression in this patient population.

"The study was clever, in that there were two primary endpoints: The first primary endpoint was clinical remission, and immunosuppression seemed to have worked, as kidney function remained reasonably stable and proteinuria declined in a subset of patients in patients randomized to that study arm," Dr Gharavi said.

However, given that both groups lost approximately 25% of kidney function during the 3-year trial, the second primary endpoint suggested that the trial was negative, he added, and there was not enough detail in the study to ascertain what factors were driving the two primary endpoints.

"On the other hand, there are many positive things about the study," Dr Gharavi said.

First, of more than 300 patients who appeared to have uncontrolled IgA nephropathy at baseline, about one third of them were no longer eligible for trial participation because their proteinuria was substantially attenuated simply with intensive blood pressure control with an angiotensin-converting-enzyme inhibitor or an angiotensin receptor blocker combined with dietary counseling and cholesterol-lowering therapy.

"This tells us that we have a lot of margin for treating our patients and that we can treat about one third of them without immunosuppressive therapy," he explained.

On the other side of the spectrum, patients with more than 3.5 g proteinuria a day were excluded from the study, and in Dr Gharavi's view, most people would still like to treat these patients with immunosuppressants.

"At 3 years, it is disappointing that immunosuppression did not have an effect on kidney function, but because IgA nephropathy is a slowly progressive disease, it may take a larger trial and 5, 10, 20 years to really see what happens to patient outcomes, so longer follow-up is needed," he said.

"These data further underscore the notion that IgA nephropathy is a heterogeneous disease," he added.

"And while I don't think we can quite stop judicious use of immunosuppressants in patients who don't respond to supportive care, these data seem to suggest that a subset of patients will respond to immunosuppressive therapy and will have stable kidney function at 3 years, whereas another subgroup may be resistant and will progress, therefore requiring alternative approaches," said Dr Gharavi.

"We need to do a better job of identifying patients at highest risk of progression, perhaps with a genetic or biomarker profile."

Dr Rauen and colleagues presented their results earlier this year at the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 52nd Congress.

The study was supported by a grant from the German Federal Ministry of Education and Research. Dr Rauen reports receiving grant support from the German Federal Ministry of Education and Research during the conduct of the study. The other authors and Dr Gharavi have disclosed no relevant financial relationships.

N Engl J Med. 2015;373:2225-2236. Abstract

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